Oct., 1945
ORIENTATION IN
THE
ribonic acid tetraacetate, its amide, chloride and methyl ester. The latter is recorded for the first time and improved directions for the preparation of the chloride are cited. 2. Reaction of D-ribonyl chloride tetraacetate with diazomethane yielded I -diazo-1-desoxy-ketowpsicose tetraacetate (11). 3. keto-D-Psicose pentaacetate and l-desoxyketo-D-psicose tetraacetate have been synthesized from 11. 4. D-Psicose has been prepared in amorphous
[CONTRIBUTION FROM
THE SCHOOL OF
1,~-BENZODIOXOLE SERIES
1797
form from its keto-acetate and characterized as its crystalline phenylosazone and phenyl osotriazole. 1-Desoxy-D-psicose(amorphous) likewise has been synthesized from its keto-acetate and characterized as its crystalline phenylosazone. 5 . The I-chloro-, 1-bromo- and 1-iodo- derivatives of keto-D-psicose tetraacetate have been synthesized. ti. A systematic nonienclature for ketoses is proposed. COLUMBUS, OHIO
CHEMISTRY O F
THE
RECEIVED AUGUST20, 1945
UNIVERSITY OF MINNESOTA]
Orientation in the 1,3-Benzodioxole Series BY RICHARD T. ARNOLD AND NEWhfAN BORTNICK~ The unusual tendency for direct nuclear substitution to occur almost exclusively a t the para positions in 1,3-benzodioxole to give $6-disubstituted-1,3-benzodioxoles(type I below) is well known.2
/o\d'x Y
dO'UX \& \y
CHI \O/'
I I1 As a result of this preferred orientation, compounds related to type I1 are not readily accessible and are generally prepared by indirect methods. In an earlier publicationS dealing with the synthesis of comparable isomeric pairs in the veratrole series, it was shown that the Claisen thermal rearrangement of allyl phenyl ethers could be used for the synthesis of compounds related to substances I and I1 (x = hydroxyl; y = allyl) from a common intermediate (111). We have now proved that the procedure emplayed in the veratrole series3 can be applied with equal success to the synthesis of 1,3-benzodioxoles as outlined in the reaction diagram (p. 1798). Some interest has been shown in the possible analgesic action of the acetoxy acids ("aspirins") in the veratrole and 1,3-benzodioxole series.6 These substances have been prepared by careful oxidation of the corresponding acetoxyaldehydes2v4although attempts t o acetylate the hydroxy acids directly in the usual manner have been u n s u ~ c e s s f u l . ~ ~ ~ Incidental t o the main study reported in this paper, we have been able to show that the failures mentioned above are due to the remarkable rapidity with which the acetoxy acids undergo hydrolysis and not due to the inability of ef(1) (2) (3) 14) (5)
Sharp and Dohme Fellow, 1942-1944. Arnold and Bordwell, Tars JOURNAL, 64, 2983 (1942). Arnold and Bortnick, ibid., 67, 806 (1945). Robertson and Head, J . Chcm. Soc., 2434 (1930). Bogcrt snd Elder, Tnra JOURNAL, 61, 534 (1929).
fecting the acetylation of the hydroxy acids. When the acetylation is brought about by acetic anhydride, good yields of the acetosy acids are obtained if the excess acetic anhydride ,is hydrolyzed a t low temperatures as described in the experirfiental section. Acknowledgment.-The authors greatly appreciate the financial aid furnished by Sharp and Dohme, Incorporated, and the interest shown by Drs. James Sprague and hl. L. Moore. Experimental 6-Carbomethoxy-5-allyloxy-l,3-benzodioxole.--Allylation of 6-carbomethoxy-5-hydroxy-l,3-benzodioxole was effected with allyl bromide and potassium carbonate in acetone solution iu a manner identical to that used in the veratrole series3; yield 96.5%; m. p. 73-73.5'. A mixture of ether and petroleum ether (b. p. 28-38') was useJ as solvent in the recrystallization. Anal. Calcd. for C12H120a: C, 61.06; H,5.13. Fouiid: C, 61.29; H, 5.33.
4-Allyl-5-hydroxy-6-carbomethoxy-l,3-benzodioxole.The above allyloxy ester (20 9.) was heated a t 180-215" for five hours in a nitrogen atmosphere. The product was distilled in a sausage flask a t reduced pressure (16 mm.) ; yield 16.5g.; m. p. 51-55". Three recrystallizations from dilute methanol gave the analytical sample; m. p. 54-56 '. Anal. Calcd. for C l ~ H l ~ OC, s : 61.06; H, 5.13. Found: C, 61.19; H, 5.45. Saponification of this ester with dilute potassium hydroside gave 5-allyl-6-hydroxypiperonylicacid ; m. p. 169-170" (dec.). Anal. Calcd. for C11HloOs: C, 59.50; H, 4.55. Found: C, 59.45; H, 4.45. 4-Propyl-5-hydroxy-I ,3-benzodioxole-6-carboxylicAcid. -When 4-allyl-5-hydroxy-6-carbomethoxy-l,3-benzodioxole (16 g.) was dissolved in methanol (100 cc.) and shaken with hydrogen a t forty pounds pressure in the presence of Adams catalyst (100 mg.), the theoretical uptake of hydrogen required only four minutes. The precipitated propyl ester was redissolved by warming the solution. After removing the catalyst on a filter, the filtrate was boiled with excess potassium hydroxide (10%). During this time the methanol was slowly removed by distillation. Acidifcation and crystallization of the product from dilute acetic acid gave 12 g. of pure product; m. p. 168-169' (dec.). Anal. Calcd. for C11HlrOl: C, 58.97; H,5.40. Found: C, 58.78; H, 5.33.
RICHARDT.ARNOLDAND NEWMAN BORTNICK
1788
VOl. 67
3
4-Propyl-5-hydroxy-l,3-benzodioxole.-Decarboxylation of 4-allyl-5-hydroxy-l,3-benzodioxole6-carboxylic acid was effected by heating the acid (3.5 9.) in dimethylaniline (5 cc.) a t its boiling point for one hour. The cooled solution was dissolved in benzene and extracted with hydrochloric acid (10%). After removal of the benzene, the product was distilled in a sausage flask under reduc:d pressure (11 mm.); yield 2.4 g. (86%); m. p. 71.5-73.5 . Anal. Calcd. for CloHlaOs: C, 67.41; H, 5.66. Found: C, 67.01; H, 5.40. Hydrogenation of this product (1.5 9.) in methanol using Adams catalyst (10 mg.) was rapid. The solution was filtered, the solvent removed by distillation and the resulting 4-propyl-5-hydroxy-l,3-benzodiaxole purified by distillation in a-, sausage flask a t reduced pressure (11 mm.); m. p. 74-76 . Anal. Calcd. for CtoHlzOa: C, 66.64; H, 6.70. Found: C, 66.67; H, 6.72. 5-Allyloxy-1,3-benzodioxolea-earboxylic Acid.-5-Allyloxy-6carhomethoxy-l,3-benzodioxole (0 g.) was dlssolved in a solution of potassium hydroxide (75 cc., 15%), and ethanol (25 cc.) and heated a t the boiling point for one hour. The ethanol was removed by distillation and the cooled aqueous solution was acidified. The collected precipitate was recrystallized from dilute acetic acid; m. p. 115-116'; wt. 5 1 g. Anal. Calcd. for CllHloOs: C, 59.50; H, 4.55. Found: C, 59.45; H, 4.88. 5-Hydroxy-6-allyl-1,3-benzodioxole.-When 5-allyloxy1,3-benzodioxole-6-carboxylicacid (2 8.) was boiled in dimethylaniline for one hour in an atmosphere of nitrogen, decarboxylation and rearrangement occurred simultaneously. Removal of the dimethylaniline in the usual manner and distillation of the residue gave a pure product; yield 84%; m. p. 71.5-73.5'. When admixed With 4allyl-5-hydroxy-1,3-benzodioxolethe melting point was below 58". Anal. Calcd. for C10H1003: C, 67.41; H, 5.66. Found: C. 117.44; H, 5.45.
Hydrogenation of this product a t low pressure with platinum gave 5-hydroxy-6-propyl-l,3-benzodioxole;m. p. 71-72 O . 6 When admixed with 5-hydroxy-6-allyl-l,3benzodioxole, the resulting sample melted a t 5&61°. 5-Methoxy-l,3-benzodioxolt6-carboxylic Acid.-5-Hydroxy-6-carbomethoxy-l,3-benzodioxole(5 g.), dimethyl sulfate (9 g.), potassium carbonate (14 g.) and dry benzene (100 cc.) were stirred and heated under reflux for forty-eight hours. The warm solution was filtered and upon evaporation of the solvent methyl 6-methoxypiperonylate separated in large prisms; m. p. 73-75'. Saponscation with methanolic potas$um hydroxide gave the acid; yield 80%; m. p. 148-149 . Anal. Calcd. for CoHaOb: C,55.15; H, 4.11. Found: C, 55.43; H, 4.11. 6.Acetoxyveratric Acid.+-Hydroxyveratric acid (5.0 9.) was dissolved in acetic anhydride (20 cc.) with heating. After cooling the solution to room temperature, two drops of concentrated sulfuric acid were added and the solution was allowed to stand for forty hours. Water (60cc.) was added and the flask was placed in a refrigerator at 0' for twenty-four hours. The precipitate was removed by filtration and recrystallFd from acetone-benzene ; yield 3.0 g.; m. p. 160-160.5 . Anal. Calcd. for CllH1206: C, 55.00; H, 5.04. Found: C, 54.85; H, 5.21. * 5-Hydroxy-1,3-benzodioxole-6-carboxylicacid (4.4 g.) was acetylated in a similar manner. Acetylation was complete in a few hours; yield 5.5 g. (93%); m. p. 150-152" (dec.).
Summary Two pairs of isomeric 4,5- and 5,6-&substituted1,3-benzodioxoles have been prepared from a common intermediate. MINNEAPOLIS 14, MINN.
RECEIVED MAY17, 1945
(6) Thorns and Bilts, Arch. Pharm., 94S, BO (1804).
